My laboratory has recently demonstrated engraftment from bone marrow cells of fully differentiated pneumocytes in mice and hepatocytes in mice and humans. This remarkable discovery and those of others showing a previously unexpected level of differential plasticity of stem cell, open up many new avenues of research. In order to efficiently address the critical questions in this new broad field of stem cell plasticity, I have brought together a group of experienced researchers, each of whom has clinical or scientific expertise in a different organ system. The focus for this proposal is to determine the cellular and biological mechanisms that induce the bone marrow cells to differentiate into epithelial cell, and to use stem cell plasticity as a therapeutic moiety by autologous transplantation of gene modified cells. In order to dissect the mechanisms of this phenomenon in vivo, I will first determine whether epithelial engraftment as liver, lung, and skin cells can be directed in vivo in mice and in humans by induction of tissue repair mechanisms in response to injury or disease. Identification of the cellular and biological mechanisms by which bone marrow cells differentiate into hepatocytes will require the development of in vitro systems in which bone marrow derived cells become liver cells. I will use three dimensional collagen system and organ culture to achieve this differentiation in vitro. Finally, using viral vectors to infect bone marrow stem cells, I will use an autologous/syngeneic transplantation model to obtain liver specific gene expression in vivo.